Aminoglycosides are among the most commonly used broad-spectrum antibiotics. They are often used clinically in combination with other antibiotics, such as β-lactams, as the first line of defense against serious infections caused particularly by various Gram-negative bacteria [(a) Wright, G. D.; Berghuis, A. M.; Mobashery, S. Resolving the Antibiotic Paradox, edited by Rosen and Mobashery, Kluwer Academic/Plenum Publishers, New York, 1998. p. 27-69. (b) Coates, A.; Hu, Y.-M.; Bax, R.; Page, C. Nat. Rev. (Drug Discovery) 2002, 1, 895-910. (c) Vakulenko, S. B.; Mobashery, S. Clin. Microbiol. Rev. 2003, 16, 430-450.]
Structurally, aminoglycosides often comprise a central 2-deoxystreptamine aminocyclitol ring to which amino sugars are linked through α-glycosidic bonds either at positions 4 and 5 (e.g. neomycin B) or at positions 4 and 6 as is the case for gentamicin C1 and kanamycin A.
At physiological pH, the amino groups of aminoglycosides are protonated polycations. It is demonstrated that the main intracellular site of action of aminoglycosides is the ribosome, particularly the major groove of polyanionic 16S rRNA on the 30S ribosome of prokaryotic cells thereby disrupting protein biosynthesis. [(a) Recht, M. I.; Douthwaite, S.; Puglisi, J. D. The EMBO J. 1999, 18, 3133-3138. (b) Fourmy, D.; Recht, M. I.; Blanchard, S. C.; Puglisi, J. D. Science 1997, 274, 1367-1375. (c) Fourmy, D.; Recht, M. I.; Puglisi, J. D. J. Mol. Biol. 1998, 277, 347-362]. Inhibition of protein synthesis may not be the sole mechanism for the bactericidal activity of aminoglycoside antibiotics. For example, it is known that aminoglycosides displace cations noted for linking liposaccharides of Gram-negative bacteria.
The global emergence of bacterial resistance to aminoglycoside antibiotics is severely limiting widespread use. Bacterial resistance mitigates clinical efficacy in severe infections, thus creating a pressing need for the discovery and development of structurally novel and potent antibiotics against aminoglycoside-resistant strains. [Walsh, C. Nat. Rev. (Microbiology) 2003, 1, 65-70]. One approach to circumvent bacterial resistance is through derivatization of existing antibiotics [(a) Tok, J. B.-H.; Bi, L.-R. Curr. Topics Med. Chem. 2003, 3, 1001-1019 and references therein. (b) Seeberger, P. H.; Baumann, M.; Zhang, G.-T.; Kanemitsu, T.; Swayze, E. E.; Hofstadler, S. A.; Griffey, R. H. Synlett. 2003, 9, 1323-1326; [(a) Hanessian, S.; Tremblay, M.; Swayze, E. E. Tetrahedron. 2003, 59, 983-993. (b) Hanessian, S.; Tremblay, M.; Kornienko, A.; Moitessier, N. Tetrahedron, 2001, 57, 3255-3265. (c) Yao, S.-L.; Sgarbi, P. W. M.; Marby, K. A.; Rabuka, D.; O'Hare, S. M.; Cheng, M. L.; Bairi, M.; Hu, C.-Y.; Hwang, S.-B.; Hwang, C.-K.; Ichikawa, Y.; Sears, P.; Sucheck, S. J. Bioorg. Med. Chem. Lett. 2004, 14, 3733-3738. (d) Venot, A.; Swayze, E. E.; Griffey, R. H.; Boons, G.-J. Chem Bio Chem 2004, 5, 1228-1236.]
Derivatization of specific functional groups often prevents enzymatic inactivation of aminoglycosides without compromising antibacterial activity [Tok, J. B.-H.; Cho, J.-H.; Rando, R. R. Tetrahedron, 1999, 55, 5741-5748]. For example, dimerization of aminoglycosides has led to better activity against resistant strains [(a) Agnelli, F.; Sucheck, S. J.; Marby, K. A.; Rabuka, D.; Yao, S.-L.; Seras, P. S.; Liang, F.-S.; Wong, C.-H. Angew. Chem. Int. Ed. 2004, 43, 1562-1566. (b) Michael, K.; Wang, H.; Tor, Y. Bioorg. Med. Chem. Lett. 1999, 7, 1361-1371]. However, naturally occurring aminoglycosides are complex molecules and are often difficult to modify chemically. The judicious protection of functional groups is critical to selective derivatization, but is laborious [(a) Haddad, J.; Kotra, L. P.; Llano-Sotelo, B.; Kim, C.-K.; Azucena Jr, E. F.; Liu, M.-Z.; Vakulenko, S. B.; Chow, C. S.; Mobashery, S. J. Am. Chem. Soc. 2002, 124, 3229-3237. (b) Roestamadji, J.; Mobashery, S. Bioorg. Med. Chem. Lett. 1998, 8, 3483-3488]. Wong and others have developed a strategy based on the neamine scaffold and azido chemistry, to generate several neamine-based aminoglycoside analogs that exhibit good antibacterial activity against resistant strains [(a) Alper, P. B.; Huang, S.-C.; Wong, C.-H. Tet. Lett. 1996, 37, 6029-6032.; (b) Chou, C. H.; Wu, C. S.; Chen, C. H.; Lu, L. D.; Kulkarni, S. S.; Wong, C.-H. Huang, S. C. Org. Lett. 2004, 6, 585-588. (c) Greenberg, W. A.; Priestley, E. S.; Seras, P. S.; Aper, P. B.; Rosenbohm, C.; Hendrix, M.; Hung, S. C.; Wong, C.-H. J. Am, Chem. Soc., 1999, 121, 6527-6541. (d) Park, W. K. C.; Auer, M.; Jaksche, H.; Wong, C.-H. J. Am. Chem. Soc. 1996, 118, 10150-10155. (e) Ding, Y.-L.; Hofstadler, S. A.; Swayze, E. E.; Risen, L.; Griffey, R. H. Angew. Chem, Int. Ed. 2003, 42, 3409-3412. (f) Ding, Y.-L.; Swayze, E. E.; Hofstadler, S. A.; Griffey, R. H. Tet. Lett. 2000, 41, 4049-4052. (g) Verhelst, S. H. L.; Magnee, L.; Wennekes, T.; Wiedenhof, W.; van der Marel, G. A.; Overkleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H. Eur. J. Org. Chem. 2004, 2402-2410]. In spite of the recent advancements, regioselective modifications of aminoglycosides remain challenging. Chemically modified aminoglycosides may either be devoid of bactericidal activity or in other cases can have greater intrinsic toxicity. Chemically modified aminoglycosides are also more expensive to produce.
An alternative approach toward overcoming antibiotic resistance involves the suppression of the resistance-mediated processes. Inhibiting the enzymes responsible for causing drug resistance has proven to be a viable approach for overcoming bacterial resistance. For example the combination of a β-lactamase inhibitor (clavulinate) and a β-lactam antibiotic, has become front line therapy for fighting β-lactam resistant bacteria [(a) Draker, K-A.; Wright, G. D. Biochemistry 2004, 43, 446-454. (b) Draker, K.-A.; Northrop, D. B.; Wright, G. D. Biochemistry 2003, 42, 6565-6574].
The common mechanism associated with resistance to antimicrobial aminoglycosides is associated with bacterial expression of drug-modifying enzymes such as adenylyltransferases, phosphoryltransferases, and acetyltransferases [Davies, J.; Wright, G. D. Trends Microbiol 1997, 5, 234]. Among these, aminoglycoside 6′-N-acetyltransferases (AAC(6′)s) are some of the most frequent drug modifying enzymes observed in clinical isolates. These enzymes exert their effect by transferring an acetyl group from acetyl coenzyme A (AcCoA) to the 6′-N of aminoglycosides thereby rendering the aminoglycoside ineffective as illustrated for kanamycin A.
In clinical isolates of aminoglycoside-resistant strains, N-acetyltransferase is one of the most frequently observed cause of resistance [(a) Wright, G. D.; Ladak, P. Antimicrob. Agents Chemother. 1997, 41, 956-960. (b) Boehr, D. D.; Daigle, D. M.; Wright, G. D. Biochemistry. 2004, 43, 9846-9855. (c) Culebras, E.; Martinez, J. L. Front. Biosci. 1999, 4, D1-D8. (d) Magnet, S.; Lambert, T.; Courvalin, P.; Blanchard, J. S. Biochemistry 2001, 40, 3700-3709. (e) Magnet, S.; Smith, T.-A.; Zheng, R.; Nordmann, P.; Blanchard, J. S. Antimicrob. Agents Chemother. 2003, 47, 1577-1583. (f) Li, X.-Z.; Zhang, L.; McKay, G. A.; Poole, K. J. Antimicrob. Chemother. 2003, 5, 803-811]. Examples of known AAC(6′)s include, but are not limited to AAC(6′)-li, AAC(6′)-APH(2″), AAC(6′)-le, AAC(6′)-ly, AAC(6′)-29b, and AAC(6′)-lz.
Compounds characterized as bi-substrate analogues have been previously considered as potential inhibitors of, for example, serotonin acetyltransferase [Kim, C. M.; Cole, P. A. J. Med. Chem. 2001, 44, 2479-2485] and GCN5 histone acetyltransferase [(a) Poux, A. N.; Cebrat, M.; Kim, C. M.; Cole, P. A.; Marmorstein, R. Proc. Nat. Acad. Sci. 2002, 99, 14065-14070. (b) Sagar, V.; Zheng, W.-P.; Thompson, P.; Cole, P. A. Bioorg. Med. Chem.y 2004, 12, 3383-3390.]. Williams et al. have described the gentamicin acetyltransferase I-catalyzed transfer of a chloroacetyl group to generate exclusively 3-N-chloroacetylgentamicin. This derivative subsequently undergoes attack by the CoA thiol thus generated, to produce the bi-substrate analogs gentamicyl-3-N-acetyl CoA [Williams, J. W.; Northrop, D. B. J. Antibiotic 1979, 32, 1147-1154]. Gao et al. have reported first generation AAC(6′)-li inhibitors that are bi-substrate analogs [Gao, F.; Yan, X.; Shakya, T.; Baettig, O. M.; Ait-Mohand-Brunet, S.; Berghuis, A. M.; Wright, G. D.; Auclair, K. J. Med. Chem, 2006, 49, 5273]. U.S. Pat. No. 7,626,005 teaches a class of aminoglycoside acetyltransferase inhibitors characterized as coenzyme A conjugated to the 6′-NH2 of an aminoglycoside. However, these first generation AAC(6′)-li inhibitors are charged high molecular weight species. There are limitations to the utility of charged high molecular weight compounds including but not limited to poor capacity or inability to permeate cell membranes, necessary to exert inhibition of aminoglycoside 6′-N-acetyltransferases.
There thus remains a need for inhibitors of aminoglycoside 6′-N-acetyltransferases. More specifically, there remains a need for inhibitors of aminoglycoside 6′-N-acetyltransferases capable of reversing or inhibiting bacterial resistance to aminoglycoside antibiotics. There further remains a need for compounds that permeate infected cells and inhibit aminoglycoside 6′-N-acetyltransferases intracellularly, thereby restoring efficacy of aminoglycoside antimicrobial agents.
Prodrugs are characterized as compounds that are pharmacologically inert but are activated in vivo by some biological mechanisms. Activation can take place for example enzymatically either extracellularly or intracellularly. Typically, the strategy to design prodrugs is often applied to overcome limitations relating to absorption, distribution, metabolism, and excretion.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.